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Intimal stiffening has been linked with increased vascular permeability and leukocyte transmigration, hallmarks of atherosclerosis. However, recent evidence indicates age-related intimal stiffening is not uniform but rather characterized by increased point-to-point heterogeneity in subendothelial matrix stiffness, the impact of which is much less understood. To investigate the impact of spatially heterogeneous matrix rigidity on endothelial monolayer integrity, we develop a micropillar model to introduce closely-spaced, step-changes in substrate rigidity and compare endothelial monolayer phenotype to rigidity-matched, uniformly stiff and compliant substrates. We found equivalent disruption of adherens junctions within monolayers on step-rigidity and uniformly stiff substrates relative to uniformly compliant substrates. Similarly, monolayers cultured on step-rigidity substrates exhibited equivalent percentages of leukocyte transmigration to monolayers on rigidity-matched, uniformly stiff substrates. Adherens junction tension and focal adhesion density, but not size, increased within monolayers on step-rigidity and uniformly stiff substrates compared to more compliant substrates suggesting that elevated tension is disrupting adherens junction integrity. Leukocyte transmigration frequency and time, focal adhesion size, and focal adhesion density did not differ between stiff and compliant sub-regions of step-rigidity substrates. Overall, our results suggest that endothelial monolayers exposed to mechanically heterogeneous substrates adopt the phenotype associated with the stiffer matrix, indicating that spatial heterogeneities in intimal stiffness observed with age could disrupt endothelial barrier integrity and contribute to atherogenesis.
Although awareness of familial hypercholesterolemia (FH) is increasing, this common, potentially fatal, treatable condition remains underdiagnosed. Despite FH being a genetic disorder, genetic testing is rarely used. The Familial Hypercholesterolemia Foundation convened an international expert panel to assess the utility of FH genetic testing. The rationale includes the following: 1) facilitation of definitive diagnosis; 2) pathogenic variants indicate higher cardiovascular risk, which indicates the potential need for more aggressive lipid lowering; 3) increase in initiation of and adherence to therapy; and 4) cascade testing of at-risk relatives. The Expert Consensus Panel recommends that FH genetic testing become the standard of care for patients with definite or probable FH, as well as for their at-risk relatives. Testing should include the genes encoding the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9); other genes may also need to be considered for analysis based on patient phenotype. Expected outcomes include greater diagnoses, more effective cascade testing, initiation of therapies at earlier ages, and more accurate risk stratification.
Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
The eMERGE Network is establishing methods for electronic transmittal of patient genetic test results from laboratories to healthcare providers across organizational boundaries. We surveyed the capabilities and needs of different network participants, established a common transfer format, and implemented transfer mechanisms based on this format. The interfaces we created are examples of the connectivity that must be instantiated before electronic genetic and genomic clinical decision support can be effectively built at the point of care. This work serves as a case example for both standards bodies and other organizations working to build the infrastructure required to provide better electronic clinical decision support for clinicians.
The development of new knowledge around the genetic determinants of variable drug action has naturally raised the question of how this new knowledge can be used to improve the outcome of drug therapy. Two broad approaches have been taken: a point-of-care approach in which genotyping for specific variant(s) is undertaken at the time of drug prescription, and a preemptive approach in which multiple genetic variants are typed in an individual patient and the information archived for later use when a drug with a "pharmacogenetic story" is prescribed. This review addresses the current state of implementation, the rationale for these approaches, and barriers that must be overcome. Benefits to pharmacogenetic testing are only now being defined and will be discussed.
© 2018 American Society for Clinical Pharmacology and Therapeutics.
Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is one of the most devastating of adverse drug reactions (ADRs) and was, until recently, essentially unpredictable. With the discovery of several risk alleles for drug-induced SJS/TEN and the demonstration of effectiveness of screening in reducing incidence, the stage is set for implementation of preventive strategies in populations at risk. Yet much remains to be learned about this potentially fatal complication of commonly used drugs.
© 2017 American Society for Clinical Pharmacology and Therapeutics.
OBJECTIVES - This multicenter pragmatic investigation assessed outcomes following clinical implementation of CYP2C19 genotype-guided antiplatelet therapy after percutaneous coronary intervention (PCI).
BACKGROUND - CYP2C19 loss-of-function alleles impair clopidogrel effectiveness after PCI.
METHODS - After clinical genotyping, each institution recommended alternative antiplatelet therapy (prasugrel, ticagrelor) in PCI patients with a loss-of-function allele. Major adverse cardiovascular events (defined as myocardial infarction, stroke, or death) within 12 months of PCI were compared between patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy. Risk was also compared between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy. Cox regression was performed, adjusting for group differences with inverse probability of treatment weights.
RESULTS - Among 1,815 patients, 572 (31.5%) had a loss-of-function allele. The risk for major adverse cardiovascular events was significantly higher in patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy (23.4 vs. 8.7 per 100 patient-years; adjusted hazard ratio: 2.26; 95% confidence interval: 1.18 to 4.32; p = 0.013). Similar results were observed among 1,210 patients with acute coronary syndromes at the time of PCI (adjusted hazard ratio: 2.87; 95% confidence interval: 1.35 to 6.09; p = 0.013). There was no difference in major adverse cardiovascular events between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy (adjusted hazard ratio: 1.14; 95% confidence interval: 0.69 to 1.88; p = 0.60).
CONCLUSIONS - These data from real-world observations demonstrate a higher risk for cardiovascular events in patients with a CYP2C19 loss-of-function allele if clopidogrel versus alternative therapy is prescribed. A future randomized study of genotype-guided antiplatelet therapy may be of value.
Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
Melanoma is the deadliest form of skin cancer and presents a significant health care burden in many countries. In addition to ultraviolet radiation in sunlight, the main causal factor for melanoma, genetic factors also play an important role in melanoma susceptibility. Although genome-wide association studies have identified many single nucleotide polymorphisms associated with melanoma, little is known about the proportion of disease risk attributable to these loci and their distribution throughout the genome. Here, we investigated the genetic architecture of melanoma in 1,888 cases and 990 controls of European non-Hispanic ancestry. We estimated the overall narrow-sense heritability of melanoma to be 0.18 (P < 0.03), indicating that genetics contributes significantly to the risk of sporadically-occurring melanoma. We then demonstrated that only a small proportion of this risk is attributable to known risk variants, suggesting that much remains unknown of the role of genetics in melanoma. To investigate further the genetic architecture of melanoma, we partitioned the heritability by chromosome, minor allele frequency, and functional annotations. We showed that common genetic variation contributes significantly to melanoma risk, with a risk model defined by a handful of genomic regions rather than many risk loci distributed throughout the genome. We also demonstrated that variants affecting gene expression in skin account for a significant proportion of the heritability, and are enriched among melanoma risk loci. Finally, by incorporating skin color into our analyses, we observed both a shift in significance for melanoma-associated loci and an enrichment of expression quantitative trait loci among melanoma susceptibility variants. These findings suggest that skin color may be an important modifier of melanoma risk. We speculate that incorporating skin color and other non-genetic factors into genetic studies may allow for an improved understanding of melanoma susceptibility and guide future investigations to identify melanoma risk genes.
3D printing enables the creation of scaffolds with precisely controlled morphometric properties for multiple tissue types, including musculoskeletal tissues such as cartilage and bone. Computed tomography (CT) imaging has been combined with 3D printing to fabricate anatomically scaled patient-specific scaffolds for bone regeneration. However, anatomically scaled scaffolds typically lack sufficient resolution to recapitulate the <100 micrometer-scale trabecular architecture essential for investigating the cellular response to the morphometric properties of bone. In this study, it is hypothesized that the architecture of trabecular bone regulates osteoblast differentiation and mineralization. To test this hypothesis, human bone-templated 3D constructs are fabricated via a new micro-CT/3D inkjet printing process. It is shown that this process reproducibly fabricates bone-templated constructs that recapitulate the anatomic site-specific morphometric properties of trabecular bone. A significant correlation is observed between the structure model index (a morphometric parameter related to surface curvature) and the degree of mineralization of human mesenchymal stem cells, with more concave surfaces promoting more extensive osteoblast differentiation and mineralization compared to predominately convex surfaces. These findings highlight the significant effects of trabecular architecture on osteoblast function.
© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Impaired wound healing that mimics chronic human skin pathologies is difficult to achieve in current animal models, hindering testing and development of new therapeutic biomaterials that promote wound healing. In this article, we describe a refinement and simplification of the porcine ischemic wound model that increases the size and number of experimental sites per animal. By comparing three flap geometries, we adopted a superior configuration (15 × 10 cm) that enabled testing of twenty 1 cm wounds in each animal: 8 total ischemic wounds within 4 bipedicle flaps and 12 nonischemic wounds. The ischemic wounds exhibited impaired skin perfusion for ∼1 week. To demonstrate the utility of the model for comparative testing of tissue regenerative biomaterials, we evaluated the healing process in wounds implanted with highly porous poly (thioketal) urethane (PTK-UR) scaffolds that were fabricated through reaction of reactive oxygen species (ROS)-cleavable PTK macrodiols with isocyanates. PTK-lysine triisocyanate (LTI) scaffolds degraded significantly in vitro under both oxidative and hydrolytic conditions whereas PTK-hexamethylene diisocyanate trimer (HDIt) scaffolds were resistant to hydrolytic breakdown and degraded exclusively through an ROS-dependent mechanism. Upon placement into porcine wounds, both types of PTK-UR materials fostered new tissue ingrowth over 10 days in both ischemic and nonischemic tissue. However, wound perfusion, tissue infiltration and the abundance of pro-regenerative, M2-polarized macrophages were markedly lower in ischemic wounds independent of scaffold type. The PTK-LTI implants significantly improved tissue infiltration and perfusion compared with analogous PTK-HDIt scaffolds in ischemic wounds. Both LTI and HDIt-based PTK-UR implants enhanced M2 macrophage activity, and these cells were selectively localized at the scaffold/tissue interface. In sum, this modified porcine wound-healing model decreased animal usage, simplified procedures, and permitted a more robust evaluation of tissue engineering materials in preclinical wound healing research. Deployment of the model for a relevant biomaterial comparison yielded results that support the use of the PTK-LTI over the PTK-HDIt scaffold formulation for future advanced therapeutic studies.
The potential impact of using human genetic data linked to longitudinal electronic medical records on drug development is extraordinary; however, the practical application of these data necessitates some organizational innovations. Vanderbilt has created resources such as an easily queried database of >2.6 million de-identified electronic health records linked to BioVU, which is a DNA biobank with more than 230,000 unique samples. To ensure these data are used to maximally benefit and accelerate both de novo drug discovery and drug repurposing efforts, we created the Accelerating Drug Development and Repurposing Incubator, a multidisciplinary think tank of experts in various therapeutic areas within both basic and clinical science as well as experts in legal, business, and other operational domains. The Incubator supports a diverse pipeline of drug indication finding projects, leveraging the natural experiment of human genetics.